Glucose metabolism and hyperglycemia1–5

Dario Giugliano, Antonio Ceriello, and Katherine Esposito

ABSTRACT In the fasting condition, plasma glucose concentrations are

Islet dysfunction and peripheral insulin resistance are both present in relatively stable, which indicates that rates of glucose production
type 2 diabetes and are both necessary for the development of hy- and utilization are equal. They average 2.2 mg 䡠 kgҀ1 䡠 minҀ1
perglycemia. In both type 1 and type 2 diabetes, large, prospective (range: 1.8 to 2.6 mg 䡠 kgҀ1 䡠 minҀ1) in healthy adults after an
clinical studies have shown a strong relation between time-averaged overnight fast (1). After a meal, glucose absorption results in
mean values of glycemia, measured as glycated hemoglobin rates of exogenous glucose delivery into the circulation that can
(HbA1c), and vascular diabetic complications. These studies are the be more than twice the rate of postabsorptive endogenous glu-
basis for the American Diabetes Association’s current recom- cose production, depending on the carbohydrate content of the
mended treatment goal that HbA1c should be 쏝7%. The measure- meal and the rate and degree of glucose absorption. As glucose is
ment of the HbA1c concentration is considered the gold standard for adsorbed, endogenous glucose production is suppressed, and

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assessing long-term glycemia; however, it does not reveal any in- glucose utilization by liver, muscle, and fat accelerates (2). Thus,
formation on the extent or frequency of blood glucose excursions, exogenous glucose is assimilated, and the plasma glucose con-
but provides an overall mean value only. Postprandial hyperglyce- centration returns to approximately the fasting state.
mia occurs frequently in patients with diabetes receiving active treat- Insulin is the dominant glucoregulatory hormone. In the fast-
ment and can occur even when metabolic control is apparently good. ing state, it regulates the plasma glucose concentration primarily
Interventional studies indicate that reducing postmeal glucose ex- by restraining hepatic glucose production; higher concentra-
cursions is as important as controlling fasting plasma glucose in tions, such as those found after meals, are required to stimulate
persons with diabetes and impaired glucose tolerance. Evidence glucose utilization (3). Glucagon is a potent hyperglycemic hor-
exists for a causal relation between postmeal glucose increases and mone that acts almost exclusively on the liver to increase hepatic
microvascular and macrovascular outcomes; therefore, it is not sur-
glucose production within minutes. Ingestion of carbohydrate
prising that treatment with different compounds that have specific
elicits a prompt rise in insulin concentration and a decrease in
effects on postprandial glucose regulation is accompanied by a sig-
glucagon concentration. The increase in insulin concentrations,
nificant improvement of many pathways supposed to be involved in
which occurs before the rise in arterial glucose concentrations, is
diabetic complications, including oxidative stress, endothelial dys-
thought to be mediated largely via hormonal signals arising in the
function, inflammation, and nuclear factor-␬B activation. The goal
gastrointestinal tract (incretion effect) (4). The early insulin re-
of therapy should be to achieve glycemic status as near to normal as
lease allows increased glucose disposal during absorption and
safely possible in all 3 components of glycemic control: HbA1c, fasting
prevents hyperglycemia. If the rise in insulin concentration oc-
glucose, and postmeal glucose peak. Am J Clin Nutr 2008;
87(suppl):217S–22S.
curred only after glucose entered the circulation, much higher
concentrations of the hormone would be required to correct the
KEY WORDS Fasting hyperglycemia, postprandial hypergly- large change in glucose concentration that would result if ab-
cemia, glycated hemoglobin, type 2 diabetes, cardiovascular disease sorption were unaccompanied by an early increase in utilization.
risk, lifestyle Islet dysfunction and peripheral insulin resistance are both
present in type 2 diabetes and are both necessary for the devel-
opment of hyperglycemia. Consequent to insulin deficiency (se-
cretion or action), glucagon concentrations rise. A fall in the
INTRODUCTION insulin-to-glucagon ratio causes increased production of glucose
Maintenance of a normal plasma glucose concentration re-
1
quires precise matching of glucose utilization and endogenous From the Department of Geriatrics and Metabolic Diseases, University
glucose production or dietary glucose delivery. Glucose is de- of Naples SUN, Italy (DG and KE), and the Warwick Medical School,
rived from 3 sources: the intestinal absorption that follows the Coventry, United Kingdom (AC).
2
Presented at an ILSI Europe workshop titled “Glycemic Response and
digestion of dietary carbohydrates, glycogenolysis, and glucone-
Health,” held in Nice, France, on 6 – 8 December 2006.
ogenesis. Glucose is transported into cells through multiple met- 3
Supported in part by a Grant (Ricerca di Ateneo) from the Second Uni-
abolic pathways: it may be stored as glycogen; it may undergo versity of Naples, Italy.
glycolysis to pyruvate; finally, it may be released into the circu- 4
Address reprint requests to ILSI Europe. E-mail: publications@
lation by the liver and kidneys, the sole organs containing ilsieurope.be.
glucose-6-phosphatase, the enzyme necessary for the release of 5
Address correspondence to D Giugliano, Via S Chiara 10/L, 80138
glucose into the circulation. Naples, Italy. E-mail: [email protected].

Am J Clin Nutr 2008;87(suppl):217S–22S. Printed in USA. © 2008 American Society for Nutrition 217S
218S GIUGLIANO ET AL

by the liver (basal hyperglycemia), whereas the absolute de- GLYCATED HEMOGLOBIN AS A CARDIOVASCULAR
crease in plasma insulin concentration or action reduces glucose DISEASE RISK FACTOR
utilization in peripheral tissues (postprandial hyperglycemia). HbA1c is an easily measured biochemical marker that strongly
correlates with the level of ambient glycemia during a 2- to 3-mo
period. Tests for HbA1c are also inexpensive and can be done at
POSTPRANDIAL HYPERGLYCEMIA any time of day. The concentration of HbA1c strongly predicts the
risk of incident eye, kidney, and nerve disease in persons with
The profile of postprandial hyperglycemia is determined by type 1 and type 2 diabetes mellitus. Epidemiologic evidence also
many factors, including the timing, quantity, and composition of indicates that HbA1c is a progressive risk factor for cardiovas-
the meal; the carbohydrate content of the meal; and the resulting cular disease in both persons with diabetes and those without
secretion of insulin and inhibition of glucagon secretion. Be- diabetes. Selvin et al (18) performed a meta-analysis of 10 cohort
cause the absorption of food continues for 5 to 6 h after a meal in studies involving 7435 persons with type 2 diabetes and 3 cohort
persons with and without diabetes, the optimal time to measure studies involving 1688 persons with type 1 diabetes. For type 2
postprandial blood glucose concentrations remains an open diabetes, a 1–percentage point absolute increase in HbA1c was
question. Postchallenge hyperglycemia refers to the glucose associated with a significant 18% increase in the risk of coronary
peak after a predefined load of glucose, ie, during an oral glucose heart disease or stroke and a 28% increase in the risk of peripheral
tolerance test (OGTT). The 75-g OGTT was standardized by the vascular disease. Khaw et al (19) analyzed the relation of one
World Health Organization (5) and is now the reference test for HbA1c measurement to incident cardiovascular events in a 6-y
categorizing glucose tolerance. The relation between values of cohort study of 10 232 diabetic and nondiabetic men and women
postprandial and postchallenge hyperglycemia is poorly under- aged 45-79 y. After adjustment for other risk factors, there was a
stood, and differences depend in part on the ability of mixed significant 21% increase in cardiovascular events for every
1–percentage point increase in HbA1c concentration above 5%.

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meals containing amino acids to provoke greater insulin secre-
tion than glucose alone. In one study, glycemia at 2 h after an Similar relations were observed for total mortality (22% for men
OGTT was closely related to 2-h glycemia after a standardized and 28% for women). These results indicate that the HbA1c
meal (6), which suggests that subjects with high concentrations concentration is an independent progressive risk factor for
of postchallenge glycemia are also likely to have exaggerated incident cardiovascular events, regardless of diabetes status.
These reports also show that the HbA1c concentration can now
glucose peaks after a normal meal in daily life.
be added to the list of other clearly established indicators of
Diabetes is diagnosed when the fasting plasma glucose con-
cardiovascular disease risk, such as blood pressure and cho-
centration is consistently 욷7 mmol/L (126 mg/dL) or when the
lesterol concentration. As suggested by Gerstein (20), the
2-h plasma glucose concentration (after drinking a 75-g glucose
presence or absence of diabetes is likely to become less im-
load) is consistently 욷11.1 mmol/L (200 mg/dL). These portant than the concentration of HbA1c in the assessment of
thresholds are much higher than the “normal” fasting and 2-h cardiovascular disease risk (similar to the fact that a diagnosis of
mean glucose concentrations of 5.1 mmol/L (92 mg/dL) and hyperlipidemia has become less important than the concentration
5.4 mmol/L (97 mg/dL), respectively. These concentrations of LDL cholesterol).
were chosen because they effectively differentiated persons at
high risk of eye disease from persons at low risk (7). It is now
clear that fasting or 2-h glucose concentrations that are well
GLYCATED HEMOGLOBIN AND GLUCOSE
below the diabetes cutoffs are cardiovascular disease risk
EXCURSIONS
factors (8, 9) and that a progressive relation between glucose
and cardiovascular disease risk extends from normal glucose The measurement of HbA1c concentrations is considered the
concentrations right into the diabetes range with no clear lower gold standard for assessing long-term glycemic control at present
threshold (9, 10). and is regarded as a key therapeutic target for the prevention of
Diabetes affects an estimated 20.8 million persons in the diabetes-related complications. The HbA1c concentration, al-
United States, 7% of the current population, and the lifetime risk though a useful measure of metabolic control and the efficacy of
diabetes therapeutic interventions, is an integrated summary of
of developing diabetes for those born in 2000 is 35% (11, 12).
circadian blood glucose concentrations during the preceding
Many of these persons will develop diabetes-specific microvas-
6 – 8 wk (21). It therefore does not reveal any information on the
cular pathology in the retina, renal glomerulus, and peripheral
extent or frequency of blood glucose excursions but provides an
nerve and accelerated atherosclerotic macrovascular disease af- overall mean value only. This being the case, one can argue that
fecting the arteries that supply the heart, brain, and lower ex- the HbA1c concentration is not necessarily the best or most clin-
tremities. In both type 1 and type 2 diabetes, large, prospective ically useful glycemic indicator of the risk of complications,
clinical studies have shown a strong relation between time- particularly at the lower end of elevated HbA1c concentrations.
averaged mean values of glycemia, measured as glycated hemo- For instance, in patients in whom glucose concentrations fluctu-
globin A1c (HbA1c), and diabetic complications (13, 14). These ate markedly, the HbA1c concentration may indicate adequate
studies are the basis for the American Diabetes Association’s metabolic control; however, such patients are exposed to the
current recommended treatment goal that HbA1c should be 쏝7% risks of hypoglycemia and the possibly harmful effects of exces-
(15) However, only about one-third of patients diagnosed as sive postprandial hyperglycemic excursions.
having diabetes achieve that goal (16) and even fewer reach the The contribution of the postprandial glucose concentration to
target concentration for HbA1c of 6.5% advocated by the Amer- overall glycemic control in persons with diabetes remains largely
ican College of Endocrinology (17). undetermined. The best determinant of HbA1c concentrations in
 GLUCOSE METABOLISM AND HYPERGLYCEMIA 219S
patients with types 1 and 2 diabetes is mean daily glycemia (22, group. The reduction in carotid intima-media thickness was as-
23). However, studies indicate that postprandial hyperglycemia sociated with changes in postprandial but not fasting hypergly-
contributes up to70% of total daytime hyperglycemia (24, 25) cemia. Therefore, evidence is emerging and suggests that treat-
Therefore, it is not surprising that in the large cohort of patients ing postprandial hyperglycemia may positively affect the
with type 1 diabetes in the Diabetes Control and Complications development of cardiovascular disease.
Trial, postprandial hyperglycemia was predictive of HbA1c con-
centrations in a manner similar to that of mean daily glycemia
MECHANISMS OF HYPERGLYCEMIA-INDUCED
(22). In type 2 diabetes, a positive correlation with HbA1c con-
VASCULAR DAMAGE
centration was reported for postprandial and preprandial glucose
concentrations (23). An explanation for apparent discrepancies At least 4 major pathways are involved in hyperglycemia-
in the data was recently provided by a study showing that the induced vascular damage: enhanced polyol activity, causing sor-
contribution of postprandial glucose excursions changes with the bitol and fructose accumulation; increased formation of ad-
degree of control: the contribution of postprandial glucose in vanced glycation end products; activation of protein kinase C and
HbA1c concentration predominates in patients with fairly good nuclear factor ␬B; and increased hexosamine pathway flux.
control, whereas the contribution of fasting hyperglycemia in- There are many reasons to think that hyperglycemic states trigger
creases as glycemic control worsens (26). all of these deleterious metabolic events through a single process:
overproduction of superoxide by the mitochondrial electron-
transport chain. This elegant and unifying theory developed by
Brownlee (39) seems to indicate that activation of oxidative
POSTPRANDIAL HYPERGLYCEMIA AND stress by hyperglycemia plays a major role in the pathogenesis of
CARDIOVASCULAR DISEASE RISK diabetic complications. Because all these metabolic alterations
Many epidemiologic data show that the 2-h glucose concen- occur more particularly in endothelial cells, it has been postu-

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tration measured during an OGTT is an independent cardiovas- lated that they can result in endothelial dysfunction and contrib-
cular disease risk factor, whereas fasting glucose is not (8, 27– ute to vascular damage (40).
31). Clearly, the OGTT is nonphysiologic and cannot be equated Activation of oxidative stress plays a pivotal role in the effects
to the consumption of a meal. However, 2 studies have confirmed of the above-mentioned mechanisms and risk factors associated
that postprandial hyperglycemia is an independent risk factor for with, or induced by, sustained hyperglycemia. However, evi-
cardiovascular diseases in type 2 diabetes in the clinical setting. dence is increasing that other glycemic disorders such as rapid
The Diabetes Intervention Study showed that in type 2 diabetes glucose swings might play an important role. Emphasis has been
the 1-h postprandial glucose concentration can be used to predict given to the relation between postprandial hyperglycemia and,
the risk of myocardial infarction (32). More recently, a prospec- more generally, hyperglycemic spikes and diabetic complica-
tions. For instance, it has been established that postprandial hy-
tive study with a mean follow-up of 5 y showed that PPG is an
perglycemia induces an overproduction of superoxide that, after
independent risk factor for coronary heart disease in patients with
reacting with nitric oxide, produces a subsequent nitrosative
type 2 diabetes, particularly in women (33).
stress with generation of such metabolic derivatives as peroxyni-
Interventional trials also suggest a link between postprandial
trite and nitrotyrosine. The toxicity of these substances can lead
hyperglycemia and cardiovascular disease risk. The STOP-
to endothelial damage and, furthermore, to microvascular and
NIDDM trial showed that treatment of subjects with impaired
macrovascular complications. By reducing postprandial excur-
glucose tolerance with the ␣-glycosidase inhibitor acarbose, a
sions, oxidative and nitrosative stress can be diminished (41).
compound that specifically reduces postprandial hyperglycemia, Nitrotyrosine is thought to be a relatively specific marker of
is associated with a 36% reduction in the risk of progression to oxidative damage mediated by peroxynitrite (42) and was re-
diabetes (34), a 34% risk reduction in the development of new cently shown to be an independent predictor of cardiovascular
cases of hypertension, and a 49% reduction in the risk of cardio- disease (43). Nitrotyrosine formation is detected during acute
vascular events (35), particularly silent myocardial infarction hyperglycemia in the artery wall of monkeys (44), in working
(36). Furthermore, in a recent meta-analysis of type 2 diabetic hearts from rats during hyperglycemia (45), and in the plasma of
patients, acarbose treatment was associated with a significant healthy and diabetic subjects (46, 47). Thus, oxidative stress,
reduction in cardiovascular events compared with placebo treat- irrespective of atherosclerotic disease stages, seems to represent
ment, also after adjustment for other risk factors (37). Very re- a key phenomenon in acute vascular disease progression.
cently, the effects of 2 insulin secretagogues, repaglinide and Glucose variations over time are not limited to postprandial
glyburide, which are known to have different efficacy on post- hyperglycemic excursions, because blood glucose concentra-
prandial hyperglycemia, on carotid intima-media thickness, and tions in patients with diabetes are always fluctuating from hy-
on markers of systemic vascular inflammation in type 2 diabetic perglycemic peaks to glucose nadirs. Such fluctuations are par-
patients have been evaluated (38). After 12 mo, the postprandial ticularly marked in type 1 diabetes and, to a lesser degree, in
glucose peak was 148 앐 28 mg/dL in the repaglinide group and patients with type 2 diabetes treated with insulin. However, pa-
180 앐 32 mg/dL in the glyburide group (P 쏝 0.01). HbA1c tients with type 2 diabetes can also experience such peak and
showed a similar decrease in both groups (0.9%). Carotid intima- trough patterns with acute glucose variations. Peaks usually cor-
media thickness regression, defined as a decrease of 쏜0.020 mm, respond to maximum values after meals, particularly at mid-
was observed in 52% of the diabetic subjects receiving repaglin- morning (48), whereas troughs are observed over interprandial
ide and in 18% of those receiving glyburide (P 쏝 0.01). periods (49), especially in patients who are treated with insulin
Interleukin-6 (P ⫽ 0.04) and C-reactive protein (P ҃ 0.02) secretagogues and who are at risk of hypoglycemic episodes
decreased more in the repaglinide group than in the glyburide (50).
220S GIUGLIANO ET AL

In one study involving patients with type 2 diabetes, Monnier value of the postmeal incremental glucose peak was 70 앐 42
et al (51) measured 24-h excretion of 8-iso-prostaglandin F2␣, an mg/dL. Most importantly, all patients had the glucose peak be-
indicator of free radical production, while patients used a con- tween 30 and 60 min after meal (Figure 1). Obviously, this
tinuous blood glucose monitoring system; fasting glucose con- contrasts with the current belief that the glucose peak occurs later
centrations and HbA1c also were determined. There was a linear after a meal and the recommendation of the American Diabetes
correlation between increased free radical production and the Association to measure blood glucose 2 h after a meal (55).
magnitude of glucose fluctuations, but not with the 24-h mean Therefore, it is not surprising that treatment with various dif-
glucose concentration, fasting plasma glucose concentrations, or ferent compounds that have specific effects on postprandial glu-
even the HbA1c concentration. 8-iso-Prostaglandin F2␣ concen- cose regulation, such as fast-acting insulin analogues, secreta-
trations were 4 times higher in patients with the greatest glycemic gogues acting on first-phase insulin secretion, amylin analogues,
variability than in patients having the lowest glycemic variabil- and acarbose, is accompanied by significant improvements, not
ity. We reported that exposure of lean nondiabetic subjects to the only in oxidative stress (56 –58) but also in endothelial dysfunc-
same magnitude of glycemic excursion reported by Monnier et al tion (59 – 61), myocardial blood flow (62), inflammation (37),
(51) doubled circulating nitrotyrosine concentrations (46). and nuclear factor-␬B activation (63).
Moreover, oscillatory hyperglycemia causes more acute incre- Evidence also suggests that both postprandial hypertriglycer-
ments in plasma concentrations of some proinflammatory cyto- idemia and hyperglycemia induce endothelial dysfunction,
kines, such as interleukin-6, interleukin-18, and tumor necrosis through induction of oxidative stress (47, 64). Studies show
factor-␣, than does chronic hyperglycemia in both healthy and independent but cumulative effects of postprandial hypertriglyc-
glucose-intolerant subjects (52). All this seems strictly related to eridemia and hyperglycemia on endothelial function, which sug-
the ability of hyperglycemic spikes to reduce the availability of gests oxidative stress as the common mediator (65). This sup-
nitric oxide (53). ports a specific and direct role of postprandial hyperglycemia,
independent of lipidemia, in cardiovascular disease. Interest-

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ingly, it was shown recently that hyperlipidemia acts to generate
POSTPRANDIAL HYPERGLYCEMIA: A TARGET OF
oxidative stress in the mitochondria through the same pathways
THERAPY
as hyperglycemia (66). The evidence described up to now proves
The precise relevance of postprandial hyperglycemia in the that hyperglycemia can induce acute alterations in normal human
daily life of persons with diabetes was recently quantified (54). homeostasis. Diabetic subjects also have basal hyperglycemia,
Self-assessed daily blood glucose curves were obtained over a and it can be hypothesized that the acute effects of mealtime
1-wk period, including 18 glucose readings before and 2 h after hyperglycemia can exacerbate those produced by chronic hyper-
meals, from 3284 unselected outpatients with non-insulin- glycemia, thus contributing to the overall complexity of diabetes.
treated type 2 diabetes mellitus who attended 500 different dia- Therefore, at present, given the tendency for rapid variations
betes clinics operating throughout Italy. A postprandial blood in hyperglycemia throughout the life of patients with diabetes
glucose value 쏜8.89 mmol/L (160 mg/dL) was recorded at least (above all in the postprandial phase), it is appropriate to think that
once in 84% of patients, which indicated that postprandial hy- this may exert an important influence on the onset of diabetes-
perglycemia is a frequent phenomenon in patients with type 2 associated complications. Thus, correcting postprandial hyper-
diabetes mellitus receiving active treatment and can occur even glycemia should form part of the strategy for the prevention and
when metabolic control is apparently good. In another study, 401 management of cardiovascular disease in diabetes.
patients with type 2 diabetes were requested to monitor home
blood glucose on 3 nonconsecutive days during a period of 1 mo
(38). In particular, they assessed blood glucose just before and LIFESTYLE CHANGES
every 30 min after the main meal of the day for 2 h. The mean Unhealthy diets and a lack of physical activity have contrib-
uted to a worldwide increase in the prevalence of obesity, type 2
diabetes, and the metabolic syndrome (67). But this epidemic is
not inevitable. We know that lifestyle intervention can dramat-
ically reduce the incidence of diabetes and slow the HbA1c in-
crease in both nondiabetic and diabetic persons (68 –70). More-
over, some recent studies deal specifically with the effect of
lifestyle changes on the resolution of the metabolic syndrome, a
forerunner of type 2 diabetes and cardiovascular diseases (71).
The first study was published in 2004 on 180 overweight subjects
with the metabolic syndrome (72). After a 2-y lifestyle program
focusing mainly on a Mediterranean-style diet, the net reduction
in prevalence of the syndrome was 48%. In the participants in the
Diabetes Prevention Program (73) who had impaired glucose
tolerance at baseline, 18% of the placebo group and 38% of the
lifestyle group no longer had the syndrome at 3 y. The Dietary
Approaches to Stop Hypertension (DASH) diet used in the Ira-
nian study (74) is similar to a Mediterranean-style diet. The
FIGURE 1. Meal-related home blood glucose monitoring obtained on 3
nonconsecutive days in 401 subjects with type 2 diabetes. The profile of the weighed mean resolution of the syndrome was 24.4% for life-
blood glucose curves did not differ significantly, and the glucose peaks style changes (Figure 2). In 2 studies, resolution of the syndrome
occurred between 30 and 60 min after the meal. From reference 38. was dependent on reduction in waist circumference and weight
 GLUCOSE METABOLISM AND HYPERGLYCEMIA 221S
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The contributions of the authors were as follows—DG: collection of data, implications for treatment and monitoring of metabolic control. Diabetes
analysis of data, writing of the manuscript; AC: significant advice and con- Care 2001;24:2023–9.
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authors had any financial or personal conflicts of interest. of plasma glucose, free fatty acid, lactate, and insulin for 24 h in patients
with NIDDM. Diabetes 1988;37:1020 – 4.
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